tbuckley/cabot-search huggingface dataset:
Biodegradable nanoparticle-induced sting pathway activation for the treatment of cancer.
Authors: Joseph Podojil, Andrew Cogswell, Ming-Yi Chiang, Valerie Eaton, Igal Efergan, Tobias Neef, Dan Xu, Khyati Meghani, Yanni Yu, Sophia Orbach, Tushar Murthy, Michael Boyne, Adam Elhofy, Lonnie Shea, Joshua J. Meeks, Stephen D. Miller
Journal: Journal of Clinical Oncology (2022)

e14552 Background: Recent advances in the field of cancer immunology have highlighted the importance of the immune system for eliminating tumors. Numerous studies have shown that tumor-infiltrating immune cells such as antigen-presenting cells (APCs), T cells, and natural killer (NK) cells play critical roles in tumor control. However, the inflammatory anti-tumor immune response is counteracted by the induction of immune regulatory mechanisms within the tumor microenvironment (TME). These findings have led to the development of immune-targeted therapies, which are aimed at activating anti-tumor immune signaling pathways and enhancing anti-tumor immune function. While immunotherapies, have revolutionized the treatment of several solid tumors and leukemias, at best response rates remain low at 25%-30%, and a portion of patients eventually develop resistance to therapy leading to disease progression and mortality. Methods: We have previously reported the potent effects of 3-4 daily intravenous infusions of immune modifying poly(lactic- co-glycolic acid) (PLGA) nanoparticles, ONP-302, free from drugs or other bioactive agents, for the amelioration of acute inflammatory diseases by targeting myeloid cells. The present studies describe a novel use for ONP-302 nanoparticles, employing an altered dosing scheme to reprogram myeloid cells resulting in significant enhancement of tumor immunity. The efficacy of ONP-302 nanoparticles at inducing an anti-tumor immune response was evaluated using syngeneic mouse tumor models. Results: ONP-302 infusion decreased tumor growth via the activation of the cGAS/STING pathway within myeloid cells, and subsequently increased NK cell activation via an IL-15-dependent mechanism. Additionally, ONP-302 treatment increased PD-1/PD-L1 expression in the tumor microenvironment, thereby allowing for functionality of anti-PD-1 for treatment in the B16.F10 melanoma tumor model which is normally unresponsive to monotherapy with anti-PD-1. Conclusions: These findings indicate that ONP-302 allows for tumor control via reprogramming myeloid cells via activation of the STING/IL-15/NK cell mechanism, as well as increasing anti-PD-1 response rates.
Ancillary treatment referrals and visits after breast cancer surgery in a sociodemographically diverse population.
Authors: Vernice Hui Yan Chan, Danielle R. Heller, Elizabeth Rapp Berger, Scott Capozza, Rachel Adams Greenup, Tara B. Sanft
Journal: Journal of Clinical Oncology (2022)

1533 Background: Ancillary therapies by rehabilitative, palliative, and survivorship specialists mitigate breast cancer surgery's physical and emotional effects. Existing data suggest that patients from disadvantaged backgrounds may be less likely to receive such care. We investigated provider referrals and patient visits at a high-volume urban cancer center to identify associated sociodemographic factors and characterize which populations may not be maximally benefiting from ancillary services. Methods: Data was culled from electronic health records of surgically-treated breast cancer patients at Yale-New Haven Health System between 2010-2017. Post-operative provider referrals to Physical/Occupational Therapy, Palliative Medicine, and Survivorship Program were evaluated for associations with demographic and disease variables in univariable and multivariable logistic regression analyses. Patient utilization of referrals, defined as attending at least one consultation, were analysed similarly. Results: Among 5,496 patients identified, 2,288 (41.6%) were referred for ancillary treatments and 1,572 (28.6%) attended at least one consultation. Provider referrals were highest among patients of Hispanic and Black ancestry (57.5% and 54.9%, respectively), no health insurance (57.6%), lowest percentage high school degree for zip code (50.5%), and lowest median income for zip code (50.7%). These associations remained significant in multivariable analysis [all p&lt;0.050]. In contrast, referral utilization was greatest among patients with private insurance (70.7%), highest percentage high school degree (72.8%), and highest median household income (72.2%), in addition to Hispanic ethnicity (73.5%). In multivariable analysis, highest median household income (OR 1.45, p = 0.019) and Hispanic ethnicity (OR 1.50, p = 0.048) remained associated. Conclusions: In a large urban health system serving a diverse population, traditional markers of poor healthcare access were positively associated with provider referral for ancillary services after breast cancer surgery. However, referral did not translate to utilization, suggesting that access remains a critical barrier to therapies that target post-operative morbidity and elevate quality of life.[Table: see text]
On-treatment plasma ctDNA fraction and treatment outcomes in metastatic castration-resistant prostate cancer.
Authors: Sofie H. Tolmeijer, Emmy Boerrigter, Takayuki Sumiyoshi, Sarah Ng, Edmond Michael Kwan, Matti Annala, Inge M. van Oort, Jack A. Schalken, Nielka P. Van Erp, Alexander William Wyatt, Niven Mehra
Journal: Journal of Clinical Oncology (2022)

5051 Background: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naive metastatic castration-resistant prostate cancer (mCRPC), but primary or rapidly acquired resistance is common. Early identification of resistant disease is critical for improving management strategies. We investigated whether on-treatment changes in plasma ctDNA fraction (ctDNA%; the proportion of cell-free DNA that is tumor-derived) associate with ARPI treatment outcomes. Methods: We collected serial plasma cell-free DNA from 81 patients with mCRPC: at baseline and following 4 weeks of treatment during two prospective multi-center observational studies (NCT02426333; NCT02471469). CtDNA% was calculated by integrating deep targeted and shallow whole-genome sequencing. Samples were dichotomized at above and below 1%, and designated as high or low ctDNA%, respectively. Outcome measurements were radiographic and/or clinical progression-free survival (rcPFS) and overall survival (OS). Non-durable responses were defined as rcPFS &lt; 6 months, excluding patients with PSA progression alone (n = 3) or treatment cessation for toxicity (n = 4). Results: Median follow-up was 27.4 months (IQR 17.7-34.9). CtDNA% was high in 47/81 (58%) patients at baseline and 29/81 (36%) patients at 4 weeks. The median ctDNA% for patients with high ctDNA was 15.0% (IQR 4.9-43.8%) at baseline and 5.0% (IQR 2.0-20.6%) at 4 weeks. High baseline ctDNA% was prognostic for rcPFS and OS (Table). RcPFS and OS was shortest for patients that retained high ctDNA% at 4 weeks. However, patients converting from high to low ctDNA% at 4 weeks did not experience different outcomes to patients with low ctDNA at both timepoints. ctDNA% associations with rcPFS and OS were independent of established clinical prognostic factors. 23/27 (85%) patients experiencing non-durable responses had high ctDNA% at baseline and 4 weeks. Only 3/47 patients (6%) experiencing durable responses had high ctDNA% at both timepoints. Sensitivity and specificity for predicting non-durable response was 85% and 94%, respectively. Conclusions: Early changes in ctDNA% are strongly linked to duration of first-line ARPI treatment benefit in mCRPC and may have utility for informing clinical trials testing early therapy switches in patients unlikely to experience durable disease responses. Clinical trial information: NCT02426333; NCT02471469. [Table: see text]
A phase 1 study of serplulimab, a novel humanized monoclonal anti-PD-1 antibody, in patients with advanced solid tumors.
Authors: Ching-Liang Ho, Tsu-Yi Chao, Chia lun Chang, Hsuan-Yu Lin, Futang Yang, Qingyu Wang, Jun Zhu
Journal: Journal of Clinical Oncology (2022)

e14560 Background: Serplulimab, a novel humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T cells and showed anti-tumor activity in several xenograft models. This phase 1 study was designed to assess the safety and tolerability of serplulimab in patients with metastatic or recurrent solid tumors. Methods: This prospective, open-label, two-cohort (dose-finding cohort [up to 30 patients]; dose expansion cohort [up to 27 patients]) phase 1 study was conducted in patients with metastatic or recurrent solid tumors who had failed standard therapy. In the dose-finding cohort, Bayesian optimal interval (BOIN) design was adopted to explore the MTD of serplulimab. Patients were administered serplulimab (Q2W) at doses of 0.3, 1, 3, or 10 mg/kg via intravenous infusion until disease progression, the maximum of 1 year, withdrawal from the study, or death, whichever occurred first. In the dose expansion cohort, nine eligible patients were enrolled in each dose group to receive fixed doses of serplulimab at 200 (Q2W), 300 (Q3W) or 400 mg (Q4W). The primary objective of this study was to identify the safety profile and the MTD of serplulimab. The PK profile and the preliminary efficacy were also examined as secondary objectives. Results: Here we only report the results from the dose-finding cohort. As of July 27, 2020, 29 patients were enrolled and treated with at least one dose of serplulimab (0.3 mg/kg group, n = 3; 1 mg/kg group, n = 4; 3 mg/kg group, n = 6; 10 mg/kg group, n = 16). At baseline, the mean age of enrolled patients was 60.0 years, with a mean BMI of 24.7 kg/m 2 , a mean BSA of 1.7 m 2 , and a mean LVEF of 67.1%. All patients presented with stage IV tumors at baseline, among whom 79.3% were diagnosed with metastatic disease. Only one patient in the 3 mg/kg dose group experienced DLTs, which was reported during the first cycle. The MTD was not determined yet. Overall, 28 (96.6%) patients experienced at least one TEAE during the study, mostly of grade 1 or 2. No notable differences were observed among the dose groups with regard to the incidence of TEAEs. The most frequently reported TEAEs was decreased appetite (41.4%), fatigue (31.0%), nausea (27.6%), pyrexia (27.6%), and pleural effusion (27.6%). Minimal accumulation of serplulimab was observed following multiple dose administrations. The preliminary anti-tumor efficacy of serplulimab was demonstrated by a DCR of 60.0%, an ORR of 8.0%, and a median PFS of 107.0 days. Conclusions: In summary, serplulimab up to 10 mg/kg was well tolerated and showed promising anti-tumor activity in patients with metastatic or recurrent solid tumors. Serplulimab is currently being investigated in phase 3 studies among patients with NSCLC, SCLC, esophageal cancer, mCRC, etc. Clinical trial information: NCT03468751.
A next generation site-specific ADC targeting breast and gastric cancer.
Authors: James Italia, Zhi Li, Myer Hussain, John Boyce, Audrey Warner
Journal: Journal of Clinical Oncology (2022)

e15024 Background: Antibody drug conjugates are entering a renaissance period as a promising treatment option for a variety of cancers. Despite some success in the past few decades, developing effective ADCs remains a challenge due to extensive inefficiencies of industry standard conjugation technologies. Industry available methods can be limited by lack of site-specificity, inflexibility on the site of conjugation, and poor overall biophysical characteristics which can alter the efficacy, safety, and bioavailability of these therapeutics. BrickBio’s unique bioconjugation methodology enables precise (site-specific), flexible (offering numerous options for conjugation site and chemistry), efficient, and scalable generation of antibody-drug conjugates which overcome these limitations and achieve the full potential of this highly promising class of therapeutics. Methods: In this work, we incorporate an azide-containing UAA (unnatural amino acid) into full-length antibodies targeting receptors overexpressed in breast and gastric cancer. Specifically, we have engineered variants of IgG1 antibodies to contain the aforementioned UAA, enabling site-specific attachment of cytotoxic payloads, such as auristatins, via click chemistry to generate ADCs with homogeneous DARs. Results: The resulting BrickADCs exhibit high therapeutic efficacy against receptor-positive cell lines, particularly lines expressing low levels of HER2, in vitro as well as in mouse xenograft models. Not only are the BrickADCs 100x more potent in demonstrated cell lines, but current research indicate that they have an improved safety profile over T-DM1 and extended half-life. Conclusions: It is conclusive that the BrickADC platform enables an increased therapeutic window. In other efforts, the BrickADC platform is leveraging a new Modular Multisite Platform to address the unmet need of eventual ADC resistance by conjugating multiple distinct payloads in a homogenous fashion. Continued preclinical work is underway for these pipeline candidates as well as investigation into other target areas.
HTG transcriptome panel (HTP): An accurate and robust tool for transcriptome-wide gene expression profiling.
Authors: Melba C. Jaramillo, Greg Reinholz, Matthew Rounseville, Dominic LaRoche, Vidya Kankipati
Journal: Journal of Clinical Oncology (2022)

e15063 Background: Analysis of transcriptome-wide gene expression has the potential to provide insights into biological pathways and molecular mechanisms that regulate disease progression and treatment response. RNA-Seq is considered the gold standard for transcriptome analysis; however, it may not perform well with older, archival formalin-fixed paraffin embedded (FFPE) tissues or low-quality/low-quantity RNA. To help researchers overcome these challenges, HTG Molecular Diagnostics developed a Research Use Only, extraction-free, targeted human transcriptome panel with an automated, proprietary web-based data analysis pipeline that provides fast, accurate, and repeatable quantitative gene expression data for 19,398 protein-coding mRNA targets from lysed FFPE tissue samples or extracted RNA (eRNA). Methods: Panel precision was evaluated by Lin’s Concordance Correlation Coefficient (Lc) using FFPE tissue lysates and eRNA from FFPE and fresh frozen tissues, including FFPE blocks that were older than ten years. The accuracy of the HTP to perform differential expression analysis was assessed by comparing it to RNA-Seq using FFPE samples from different cancer indications. The agreement of the log fold changes between the two platforms was measured by Pearson Correlation Coefficient (Pc). Additionally, a cohort of 83 breast cancer FFPE samples, that had also been evaluated for estrogen (ER) and progesterone (PR) receptor expression by immunohistochemistry (IHC), were used to determine the correlation between HTP gene expression and orthogonal IHC data. Results: The precision of the panel measured by Lc, ranged from 0.90-0.94 across multiple operators, instruments, lots, and processing days, demonstrating that the HTP is a precise and robust panel. In addition, HTP is a competitive alternate to RNA-seq (estimated log-fold changes, Pc = 0.83 between the platforms). Archival samples demonstrated high repeatability (Pc &gt; 0.9) with sample pass rates of 100% for HTP, which further confirms panel’s robust performance. Furthermore, the HTP gene expression results correlated with the IHC markers for ER (Pc = 0.92) and PR (Pc = 0.88) receptor status in a cohort of 83 breast cancer samples, which highlights the potential of the panel to replace IHC staining while providing expression data on thousands of additional genes. Conclusions: The results demonstrate the HTP is a powerful tool for comprehensive gene expression analysis that addresses several key limitations of RNA-Seq. The HTP is precise, accurate, user-friendly (avoids extraction-bias, fewer steps, automated data analysis), and efficient (quicker, requires lower amounts of sample, works well with samples of low quality and archival samples). Collectively, the data demonstrate HTP has the potential to be used for biomarker discovery and the development of clinical solutions.
Low baseline vitamin D levels correlate with adverse pathological features and clinical outcomes among patients with breast cancer.
Authors: Dina Barakat, Rehab Mohamed, Maha Elnaggar, Dalia Tarik, Samir-Shehata M. Eid
Journal: Journal of Clinical Oncology (2022)

552 Background: Serum vitamin D levels have been linked to breast cancer development; however, the impact on breast cancer features and outcomes remains unclear. The present study aimed at investigating the prognostic value of baseline vitamin D level among non-metastatic breast cancer patients. Methods: In this study; we prospectively assessed female patients presenting to our department with non-metastatic breast cancer during the period from October 2018 to December 2019 for their baseline serum vitamin D levels measured by ELISA test before starting systemic therapy, in addition to other clinicopathological factors. Low Vit-D was defined as Vit-D level less than 30 ng /l. Chi-square test (Fisher’s exact test) was used to examine the relation between qualitative variables. Survival analysis was done using Kaplan-Meier method and comparison between two survival curves was done using log-rank test. Multivariate analysis was done using Cox-regression hazard model for the significant factors affecting survival on univariate analysis. Results: We enrolled 221 patients with non-metastatic breast cancer as they matched our eligibility criteria. Median age at diagnosis was (50.7± 10.9). About two thirds of the patients (64.7%) were post menopause. Median vitamin D level was (23.1 ng/l) with a range of (4-62.46 ng/liter). Around half of the patients (56.5%) had vitamin D level lower than 30 ng/liter, with higher numbers of low vitamin D levels among HER2 positive and triple negative (TNBC) patients compared to hormonal receptor positive (HR+ve) patients (P=&lt;0.001). There was a significant negative correlation between vitamin D levels and tumor size, lymph node positivity and stage at diagnosis (the lower the vitamin D level, the larger the tumor size, and the higher the number of positive lymph nodes and the stage; r= -0.414, r= -0.586, r= -0.674; respectively; p&lt;0.001). On follow up, the number of local recurrences, bone metastases and liver metastases were significantly higher among the low vitamin D level group, however; there was no significant difference between the two groups in terms of development of brain and lung metastases. Disease free survival (DFS) and overall survival (OS) was significantly worse among the low vitamin D level group (p&lt;0.001). Conclusions: Low serum vitamin D in breast cancer patients negatively correlates with tumor size, lymph node positivity and stage at diagnosis. It is linked to HER-2 positive and TNBC, and is significantly associated with worse DFS and OS.
A pan-cancer analysis of P21 activated kinase (PAK) family genes as potential biomarkers for immune checkpoint therapy.
Authors: Sun Gang, Wenjia Guo, Lei Qiao, Tonghui Sun, Yuan Tan, Qin Zhang, Qianqian Duan, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

2614 Background: PAK (P21 activated kinase) is a family of serine threonine kinases, that consist of 6 members, PAKs 1-6, which are positioned at an intersection of multiple signaling pathways implicated in oncogenesis. Recent studies have found relationship between mutations of some PAK family genes and antitumor immunity. Here, we explored the associations of PAK family gene mutations with ICI response based on multidimensional data from multiple solid tumors. Methods: An immunotherapy cohort (Broad/Dana-Farber, Nat Genet 2018, N = 249) within 7 types of tumors as discovery stage, was used to explore the association of PAK family genes mutations with tumor mutation burden (TMB) and efficacy of immunotherapy. To further validate the predictive value of PAK family genes, we employed another ICI-treated cohort, MSKCC cohort (Samstein, Nat Genet 2019, n = 1661), as a validation cohort. TMB was calculated as the total count of nonsynonymous mutations in coding sequence. Results: In discovery cohort, compared to that in the PAK-Wt group, longer OS was observed in the PAK-Mut group (mOS: 31.3 vs 15.4 months, HR = 0.59, 95% CI: 0.36 to 0.96, P= 0.03). In addition, PAK-Mut group had higher TMB ( P&lt; 0.001). Median TMB in PAK-Mut group and PAK-Wt group is 17.79 (IQR, 7.45-36.55) Mut/Mb and 5.47 (IQR, 2.46-9.09) Mut/Mb, separately. In validation cohort, PAK-Mut patients also achieved significant improved OS compared with PAK-Wt patients (mOS: 44.0 vs 17.0 months, HR = 0.51, 95% CI: 0.37 to 0.69, P&lt; 0.001). Moreover, multivariable analysis of validation cohort demonstrated that PAK-Mut was associated with better OS (HR = 0.71; 95%CI, 0.52-0.98; P = 0.036), after adjusting for Age, Gender, Metastasis, Treatment, TMB, Cancer type. Compared with PAK-Wt group (median [IQR]: 5.90 [2.95-10.04]), PAK-Mut group (median [IQR]: 21.19 [11.81-43.29]) also had higher TMB ( P&lt; 0.001). Conclusions: The results indicated that PAK family genes mutation was associated with a higher TMB both discovery and validation cohort. Analysis of discover and validation immunotherapy cohort data showed PAK family was associated with better OS. These findings indicate that these genes mutation may serve as a potential predictive biomarker for ICI in solid tumor patients.
Whole slide histologic grading of breast cancer using convolutional neural networks.
Authors: Gokhan Demir, Leonard O. Iheme, Gizem Solmaz, Cisem Yazici, Fatma Tokat, Sercan Çayır, Engin Bozaba, Muhammet Eren Tekin, Gülşah Özsoy, Samet Ayaltı, Cavit Kerem Kayhan, Ümit İnce, Burak Uzel, Huseyin Kusetogullari
Journal: Journal of Clinical Oncology (2022)

e13607 Background: The Nottingham histologic grade (NHG) is a strong prognostic factor in early-stage breast cancer. It consists of nuclear pleomorphism, tubular formation, and mitotic count. We recently developed an artificial intelligence (AI) based automatic grading system. Methods: In this study, we have retrospectively evaluated 179,651 hematoxylin and eosin-stained patches extracted from 402 digitized biopsies of 338 patients with confirmed invasive ductal carcinoma diagnosis. The data was collected at Acıbadem University Hospital between 2017 and 2021. The digitized slides were manually labeled by seven pathologists before being used to train the deep learning models (DL). The pre-trained (on ImageNet) DL architectures which are EfficientNet backbone U-Net, YOLOv5, DenseNet161, and a modified VGG-11 have been fine-tuned with this study’s dataset for the tubule segmentation, nuclei detection, mitosis classification, and the nuclear pleomorphism classification tasks, respectively. Data augmentation for boosting the accuracy was done. Semantic segmentation for tubular formation, object detection for detection of nuclei, and image classification for the mitotic count and nuclear pleomorphism was also performed. Results: The AI-based algorithms have obtained reproducible histologic scores with mean F1 scores, sensitivities, and specificities as presented in Table. Conclusions: The AI-based automatic grading system is accurate in the evaluation of the components of NHG. This system will speed up the pathology workflow in the clinic, provide decision support to pathologists and mitigate the sensitivity associated with the traditional grading process. [Table: see text]